Trifluoromethyl-substituted fused pyrimidines and their use

ABSTRACT

The present application relates to novel trifluoromethyl-substituted fused pyrimidines, to processes for their preparation, to their use alone or in combinations for the treatment and/or prophylaxis of diseases, and to their use for producing medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular disorders.

The present application relates to novel trifluoromethyl-substitutedfused pyrimidines, to processes for their preparation, to their usealone or in combinations for the treatment and/or prophylaxis ofdiseases, and to their use for producing medicaments for the treatmentand/or prophylaxis of diseases, in particular for the treatment and/orprophylaxis of cardiovascular disorders.

One of the most important cellular transmission systems in mammaliancells is cyclic guanosine monophosphate (cGMP). Together with nitrogenmonoxide (NO), which is released from the endothelium and transmitshormonal and mechanical signals, it forms the NO/cGMP system. Guanylatecyclases catalyse the biosynthesis of cGMP from guanosine triphosphate(GTP). The representatives of this family known to date can be dividedinto two groups either according to structural features or according tothe type of ligands: the particulate guanylate cyclases which can bestimulated by natriuretic peptides, and the soluble guanylate cyclaseswhich can be stimulated by NO. The soluble guanylate cyclases consist oftwo subunits and very probably contain one haem per heterodimer, whichis part of the regulatory site. This is of central importance for theactivation mechanism. NO can bind to the iron atom of haem and thusmarkedly increase the activity of the enzyme. Haem-free preparationscannot, by contrast, be stimulated by NO. Carbon monoxide (CO) is alsoable to bind to the central iron atom of haem, but the stimulation by COis much less than that by NO.

By forming cGMP, and owing to the resulting regulation ofphosphodiesterases, ion channels and protein kinases, guanylate cyclaseplays an important role in various physiological processes, inparticular in the relaxation and proliferation of smooth muscle cells,in platelet aggregation and platelet adhesion and in neuronal signaltransmission, and also in disorders which are based on a disruption ofthe abovementioned processes. Under pathophysiological conditions, theNO/cGMP system can be suppressed, which can lead, for example, tohypertension, platelet activation, increased cell proliferation,endothelial dysfunction, atherosclerosis, angina pectoris, heartfailure, myocardial infarction, thromboses, stroke and sexualdysfunction.

Owing to the expected high efficiency and low level of side effects, apossible NO-independent treatment for such disorders by targeting theinfluence of the cGMP signal pathway in organisms is a promisingapproach.

Hitherto, for the therapeutic stimulation of the soluble guanylatecyclase, use has exclusively been made of compounds such as organicnitrates whose effect is based on NO. The latter is formed bybioconversion and activates soluble guanylate cyclase by attack at thecentral iron atom of haem. In addition to the side effects, thedevelopment of tolerance is one of the decisive disadvantages of thistype of treatment.

Some years ago, a number of substances were described which stimulatesoluble guanylate cyclase directly, i.e. without prior release of NO,such as, for example, 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole[YC-1; Wu et al., Blood 84 (1994), 4226; Mülsch et al., Brit. J.Pharmacol. 120 (1997), 681]. The more recent stimulators of solubleguanylate cyclase include among others BAY 41-2272, BAY 41-8543 andriociguat (BAY 63-2521) (see, for example, Stasch J.-P. et al., Nat.Rev. Drug Disc. 2006; 5: 755-768; Stasch J.-P. et al., Chem Med Chem2009; 4: 853-865. Stasch J.-P. et al., Circulation 2011; 123:2263-2273).

As stimulators of soluble guanylate cyclase, WO 00/06568 and WO 00/06569disclose fused pyrazole derivatives, and WO 03/095451 disclosescarbamate-substituted 3-pyrimidinylpyrazolopyridines.3-Pyrimidinylpyrazolopyridines with phenylamide substituents aredescribed in E. M. Becker et al., BMC Pharmacology 1 (13), 2001. WO2004/009590 describes pyrazolopyridines with substituted4-aminopyrimidines for treatment of CNS disorders. WO 2010/065275 and WO2011/149921 disclose substituted pyrrolo- and dihydropyridopyrimidinesas sGC activators. As sGC stimulators, WO 2012/004259 describes fusedaminopyrimidines, and WO 2012/004258, WO 2013/004785 and WO 2013/030288describe fused pyrimidines and triazines. WO 2012/28647 disclosespyrazolopyridines with various azaheterocycles for treatment ofcardiovascular disorders.

It was an object of the present invention to provide novel substanceswhich act as stimulators of soluble guanylate cyclase and which have anidentical or improved therapeutic profile compared to compounds knownfrom the prior art, for example with respect to their in vivo propertiessuch as their pharmacokinetic and pharmacodynamic behaviour and/or theirmetabolic profile and/or their dose-activity relationship and/or theirside effect profile.

The present invention provides the compound having the systematic name2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-oneand the structural formula (I)

and the N-oxides, salts, solvates, salts of the N-oxides and solvates ofthe N-oxides and salts thereof.

Compounds according to the invention are the compounds of the formulae(I), (I-A) and (1-B) and their salts, solvates and solvates of thesalts, the compounds, comprised by formulae (I), (I-A) and (I-B), of theformulae mentioned below and their salts, solvates and solvates of thesalts and the compounds comprised by formulae (I), (I-A) and (I-B),mentioned below as embodiments, and their salts, solvates and solvatesof the salts, if the compounds, comprised by formulae (I), (I-A) and(I-B), mentioned below are not already salts, solvates and solvates ofthe salts.

Preferred salts in the context of the present invention arephysiologically acceptable salts of the compounds according to theinvention. Also encompassed are salts which are not themselves suitablefor pharmaceutical applications but can be used, for example, forisolation or purification of the compounds according to the invention.

Physiologically acceptable salts of the compounds according to theinvention include acid addition salts of mineral acids, carboxylic acidsand sulphonic acids, for example salts of hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, methanesulphonic acid,ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid,naphthalenedisulphonic acid, formic acid, acetic acid, trifluoroaceticacid, propionic acid, lactic acid, tartaric acid, malic acid, citricacid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds according to theinvention also include salts of conventional bases, by way of exampleand with preference alkali metal salts (e.g. sodium and potassiumsalts), alkaline earth metal salts (e.g. calcium and magnesium salts)and ammonium salts derived from ammonia or organic amines having 1 to 16carbon atoms, by way of example and with preference ethylamine,diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine,arginine, lysine, ethylenediamine and N-methylpiperidine.

In the context of the invention, solvates refer to those forms of thecompounds according to the invention which, in the solid or liquidstate, form a complex by coordination with solvent molecules. Hydratesare a specific form of the solvates in which the coordination is withwater. Preferred solvates in the context of the present invention arehydrates.

The compounds according to the invention can exist in differentstereoisomeric forms, that is in the form of configurational isomers.The present invention therefore encompasses the enantiomers and theirmixtures. The stereoisomerically uniform constituents can be isolatedfrom such mixtures of enantiomers in a known manner; chromatographyprocesses are preferably used for this, in particular HPLCchromatography on a chiral phase.

Where the compounds according to the invention can occur in tautomericforms, the present invention encompasses all the tautomeric forms.

The present invention also encompasses all suitable isotopic variants ofthe compounds according to the invention. An isotopic variant of acompound according to the invention is understood here to mean acompound in which at least one atom within the compound according to theinvention has been exchanged for another atom of the same atomic number,but with a different atomic mass than the atomic mass which usually orpredominantly occurs in nature. Examples of isotopes which can beincorporated into a compound according to the invention are those ofhydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine,chlorine, bromine and iodine, such as ²H (deuterium), ³H (tritium), ¹³C,¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S, ¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I,¹²⁴I, ¹²⁹I and ¹³¹I. Particular isotopic variants of a compoundaccording to the invention, especially those in which one or moreradioactive isotopes have been incorporated, may be beneficial, forexample, for the examination of the mechanism of action or of the activeingredient distribution in the body; due to comparatively easypreparability and detectability, especially compounds labelled with ³Hor ¹⁴C isotopes are suitable for this purpose. Furthermore, theincorporation of isotopes, for example of deuterium, can lead toparticular therapeutic advantages as a consequence of greater metabolicstability of the compound, for example an extension of the half-life inthe body or a reduction in the active dose required; such modificationsof the compounds according to the invention may therefore, in somecases, also constitute a preferred embodiment of the present invention.Isotopic variants of the compounds according to the invention can beprepared by the processes known to those skilled in the art, for exampleby the methods described below and the procedures described in theworking examples, by using corresponding isotopic modifications of therespective reagents and/or starting compounds.

Moreover, the present invention also encompasses prodrugs of thecompounds according to the invention. Here, the term “prodrugs” refersto compounds which for their part can be biologically active orinactive, but are converted (for example metabolically orhydrolytically) into compounds according to the invention during theirdwell time in the body.

In the context of the present invention, the term “treatment” or“treating” includes inhibition, retardation, checking, alleviating,attenuating, restricting, reducing, suppressing, repelling or healing ofa disease, a condition, a disorder, an injury or a health problem, orthe development, the course or the progression of such states and/or thesymptoms of such states. The term “therapy” is understood here to besynonymous with the term “treatment”.

The terms “prevention”, “prophylaxis” or “preclusion” are usedsynonymously in the context of the present invention and refer to theavoidance or reduction of the risk of contracting, experiencing,suffering from or having a disease, a condition, a disorder, an injuryor a health problem, or a development or progression of such statesand/or the symptoms of such states.

The treatment or prevention of a disease, a condition, a disorder, aninjury or a health problem may be partial or complete.

In the context of the present invention, preference is given to theenantiomer of the compound (I) having the systematic name(5R)-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-oneand the structural formula (I-A)

and the salts, solvates and solvates of the salts thereof.

In the context of the present invention, preference is given to theenantiomer of the compound (I) having the systematic name(5S)-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-oneand the structural formula (I-B)

and the salts, solvates and solvates of the salts thereof.

The invention furthermore provides a process for preparing the compoundsof the formula (I) according to the invention, characterized in that acompound of the formula (II)

is converted in an inert solvent using isopentyl nitrite and a halogenequivalent into a compound of the formula (III)

and this is then reacted in an inert solvent, optionally in the presenceof a suitable base, with a compound of the formula (IV)

to give the compound of the formula (I)

and the resulting compound of the formula (I) is optionally convertedwith the appropriate (i) solvents and/or (ii) acids or bases to thesolvates, salts and/or solvates of the salts thereof. Process step(II)→(III) is carried out with or without solvent. Suitable solvents areall organic solvents which are inert under the reaction conditions. Thepreferred solvent is dioxane.

The reaction (II)→(III) is generally carried out in a temperature rangeof from +20° C. to +100° C., preferably within the range from +50° C. to+100° C., optionally in a microwave. The reaction can be carried out atatmospheric, elevated or reduced pressure (for example in the range from0.5 to 5 bar). In general, atmospheric pressure is employed.

Suitable halogen sources in the reaction (II)→(III) are, for example,diiodomethane, a mixture of caesium iodide, iodine and copper(I) iodideor copper(II) bromide.

Inert solvents for the process step (III)+(IV)→(I) are, for example,ethers such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran,glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbonssuch as benzene, xylene, toluene, hexane, cyclohexane or mineral oilfractions, or other solvents such as dimethylformamide (DMF), dimethylsulphoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU),N-methylpyrrolidone (NMP), pyridine, acetonitrile or sulpholane. It isalso possible to use mixtures of the solvents mentioned. Preference isgiven to NMP.

The reaction (III)+(IV)→(I) is generally conducted within a temperaturerange of +20° C. to +200° C., preferably at +150° C. to +200° C.,preferably in a microwave. The reaction can be carried out atatmospheric, elevated or reduced pressure (for example from 0.5 to 5bar).

The preparation process described can be illustrated by the synthesisscheme below (Scheme 1):

The compounds of the formula (II) can be prepared by reacting a compoundof the formula (V)

in an inert solvent in the presence of a suitable base with a compoundof the formula (VI)

to give the compound of the formula (II)

Inert solvents for the process step (V)+(VI)→(II) are, for example,alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanolor tert-butanol, ethers such as diethyl ether, dioxane, dimethoxyethane,tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethylether, hydrocarbons such as benzene, xylene, toluene, hexane,cyclohexane or mineral oil fractions, or other solvents such asdimethylformamide (DMF), dimethyl sulphoxide (DMSO),N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine,acetonitrile, sulpholane or else water. It is also possible to usemixtures of the solvents mentioned. Preference is given to tert-butanol.

Suitable bases for the process step (V)+(VI)→(II) are alkali metalhydroxides such as, for example, lithium hydroxide, sodium hydroxide orpotassium hydroxide, alkali metal carbonates such as lithium carbonate,sodium carbonate, potassium carbonate or caesium carbonate, alkali metalbicarbonates such as sodium bicarbonate or potassium bicarbonate, alkalimetal alkoxides such as sodium methoxide or potassium methoxide, sodiumethoxide or potassium ethoxide or potassium tert-butoxide, or organicamines such as triethylamine, diisopropylethylamine, pyridine,1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) or1,5-diazabicyclo[4.3.0]non-5-ene (DBN). Preference is given to potassiumtert-butoxide.

The reaction (V)+(VI)→(II) is generally conducted within a temperaturerange of +20° C. to +150° C., preferably at +75° C. to +100° C.,optionally in a microwave. The reaction can be carried out atatmospheric, elevated or reduced pressure (for example from 0.5 to 5bar). In general, atmospheric pressure is employed.

The preparation process described above can be illustrated in anexemplary manner by the synthesis scheme below (Scheme 3):

The compounds of the formula (V) are known from the literature (see, forexample, WO 2013/004785, example 14A).

The compound of the formula (VI) can be prepared by reacting a compoundof the formula (VII)

in an inert solvent with methylmagnesium halide.

The compound of the formula (VII) is known from the literature (cf., forexample, Journal of Fluorine Chemistry, 1991, vol. 51, #3 pp. 323-334).

The compound of the formula (IV) is commercially available, known fromthe literature or can be prepared in analogy to literature processes.

The compounds according to the invention act as potent stimulators ofsoluble guanylate cyclase, have valuable pharmacological properties andhave an improved therapeutic profile, for example with respect to the invivo properties thereof and/or the pharmacokinetic characteristicsand/or metabolic profile thereof. They are therefore suitable for thetreatment and/or prophylaxis of diseases in humans and animals.

The compounds according to the invention cause vasorelaxation andinhibition of platelet aggregation, and lead to a decrease in bloodpressure and to a rise in coronary blood flow. These effects aremediated via direct stimulation of soluble guanylate cyclase andintracellular cGMP increase. Moreover, the compound according to theinvention enhances the effect of substances increasing the cGMPconcentration, such as, for example, EDRF (endothelium-derived relaxingfactor), NO donors, protoporphyrin IX, arachidonic acid orphenylhydrazine derivatives.

The compounds according to the invention are suitable for the treatmentand/or prophylaxis of cardiovascular, pulmonary, thromboembolic andfibrotic disorders.

Accordingly, the compounds according to the invention can be used inmedicaments for the treatment and/or prophylaxis of cardiovasculardisorders such as, for example, hypertension, resistant hypertension,acute and chronic heart failure, coronary heart disease, stable andunstable angina pectoris, peripheral and cardiac vascular disorders,arrhythmias, atrial and ventricular arrhythmias and impaired conductionsuch as, for example, atrioventricular blocks degrees I-III (AB blocksupraventricular tachyarrhythmia, atrial fibrillation, atrial flutter,ventricular fibrillation, ventricular flutter, ventriculartachyarrhythmia, Torsade de pointes tachycardia, atrial and ventricularextrasystoles, AV-junctional extrasystoles, sick sinus syndrome,syncopes, AV-nodal re-entry tachycardia, Wolff-Parkinson-White syndrome,of acute coronary syndrome (ACS), autoimmune cardiac disorders(pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies),shock such as cardiogenic shock, septic shock and anaphylactic shock,aneurysms, boxer cardiomyopathy (premature ventricular contraction(PVC)), for the treatment and/or prophylaxis of thromboembolic disordersand ischaemias such as myocardial ischaemia, myocardial infarction,stroke, cardiac hypertrophy, transient and ischaemic attacks,preeclampsia, inflammatory cardiovascular disorders, spasms of thecoronary arteries and peripheral arteries, oedema formation such as, forexample, pulmonary oedema, cerebral oedema, renal oedema or oedemacaused by heart failure, peripheral circulatory disturbances,reperfusion damage, arterial and venous thromboses, microalbuminuria,myocardial insufficiency, endothelial dysfunction, to preventrestenoses, for example after thrombolysis therapies, percutaneoustransluminal angioplasties (PTA), transluminal coronary angioplasties(PTCA), heart transplants and bypass operations, and also micro- andmacrovascular damage (vasculitis), increased levels of fibrinogen and oflow-density lipoprotein (LDL) and increased concentrations ofplasminogen activator inhibitor 1 (PAI-1), and also for the treatmentand/or prophylaxis of erectile dysfunction and female sexualdysfunction.

In the context of the present invention, the term “heart failure”encompasses both acute and chronic forms of heart failure, and also morespecific or related types of disease, such as acute decompensated heartfailure, right heart failure, left heart failure, global failure,ischaemic cardiomyopathy, dilated cardiomyopathy, hypertrophiccardiomyopathy, idiopathic cardiomyopathy, congenital heart defects,heart failure associated with heart valve defects, mitral valvestenosis, mitral valve insufficiency, aortic valve stenosis, aorticvalve insufficiency, tricuspid valve stenosis, tricuspid valveinsufficiency, pulmonary valve stenosis, pulmonary valve insufficiency,combined heart valve defects, myocardial inflammation (myocarditis),chronic myocarditis, acute myocarditis, viral myocarditis, diabeticheart failure, alcoholic cardiomyopathy, cardiac storage disorders,diastolic heart failure and systolic heart failure, and acute phases ofworsening of existing chronic heart failure (worsening heart failure).

In addition, the compound according to the invention can also be usedfor the treatment and/or prophylaxis of arteriosclerosis, impaired lipidmetabolism, hypolipoproteinaemias, dyslipidaemias,hypertriglyceridaemias, hyperlipidaemias, hypercholesterolaemias,abetalipoproteinaemia, sitosterolaemia, xanthomatosis, Tangier disease,adiposity, obesity and of combined hyperlipidaemias and metabolicsyndrome.

The compounds according to the invention can additionally be used forthe treatment and/or prophylaxis of primary and secondary Raynaud'sphenomenon, of microcirculation impairments, claudication, peripheraland autonomic neuropathies, diabetic microangiopathies, diabeticretinopathy, diabetic ulcers on the extremities, gangrene, CRESTsyndrome, erythematosis, onychomycosis, rheumatic disorders and forpromoting wound healing.

The compounds according to the invention are furthermore suitable fortreating urological disorders such as, for example, benign prostatesyndrome (BPS), benign prostate hyperplasia (BPH), benign prostateenlargement (BPE), bladder outlet obstruction (BOO), lower urinary tractsyndromes (LUTS, including Feline Urological Syndrome (FUS)), disordersof the urogenital system including neurogenic overactive bladder (OAB)and (IC), incontinence (UI) such as, for example, mixed urinaryincontinence, urge urinary incontinence, stress urinary incontinence oroverflow urinary incontinence (MUI, UUI, SUI, OUI), pelvic pain, benignand malignant disorders of the organs of the male and female urogenitalsystem.

The compounds according to the invention are furthermore suitable forthe treatment and/or prophylaxis of kidney disorders, in particular ofacute and chronic renal insufficiency and acute and chronic renalfailure. In the context of the present invention, the term renalinsufficiency comprises both acute and chronic manifestations thereof,as well as underlying or related kidney diseases such as renalhypoperfusion, intradialytic hypotension, obstructive uropathy,glomerulopathies, glomerulonephritis, acute glomerulonephritis,glomerulosclerosis, tubulointerstitial diseases, nephropathic diseasessuch as primary and congenital kidney disease, nephritis, immunologicalkidney diseases such as kidney graft rejection and immunocomplex-inducedkidney diseases, nephropathy induced by toxic substances, nephropathyinduced by contrast agents, diabetic and non-diabetic nephropathy,pyelonephritis, renal cysts, nephrosclerosis, hypertensivenephrosclerosis and nephrotic syndrome, which can be characterizeddiagnostically for example by abnormally reduced creatinine and/or waterexcretion, abnormally raised blood concentrations of urea, nitrogen,potassium and/or creatinine, altered activity of renal enzymes such as,for example, glutamyl synthetase, altered urine osmolarity or urinevolume, increased microalbuminuria, macroalbuminuria, lesions onglomerulae and arterioles, tubular dilatation, hyperphosphataemia and/orneed for dialysis. The present invention also encompasses the use of thecompounds according to the invention for the treatment and/orprophylaxis of sequelae of renal insufficiency, for example pulmonaryoedema, heart failure, uraemia, anaemia, electrolyte disturbances (forexample hyperkalaemia, hyponatraemia) and disturbances in bone andcarbohydrate metabolism.

Furthermore, the compounds according to the invention are also suitablefor the treatment and/or prophylaxis of asthmatic disorders, pulmonaryarterial hypertension (PAH) and other forms of pulmonary hypertension(PH) including left-heart disease, HIV, sickle cell anaemia,thromboembolisms (CTEPH), sarcoidosis, COPD or pulmonaryfibrosis-associated pulmonary hypertension, chronic-obstructivepulmonary disease (COPD), acute respiratory distress syndrome (ARDS),acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD),pulmonary fibrosis, pulmonary emphysema (for example pulmonary emphysemainduced by cigarette smoke) and cystic fibrosis (CF).

The compounds described in the present invention are also activecompounds for control of central nervous system disorders characterizedby disturbances of the NO/cGMP system. They are suitable in particularfor improving perception, concentration, learning or memory aftercognitive impairments like those occurring in particular in associationwith situations/diseases/syndromes such as mild cognitive impairment,age-associated learning and memory impairments, age-associated memorylosses, vascular dementia, craniocerebral trauma, stroke, dementiaoccurring after strokes (post stroke dementia), post-traumaticcraniocerebral trauma, general concentration impairments, concentrationimpairments in children with learning and memory problems, Alzheimer'sdisease, Lewy body dementia, dementia with degeneration of the frontallobes including Pick's syndrome, Parkinson's disease, progressivenuclear palsy, dementia with corticobasal degeneration, amyolateralsclerosis (ALS), Huntington's disease, demyelinisation, multiplesclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIVdementia, schizophrenia with dementia or Korsakoff's psychosis. They arealso suitable for the treatment and/or prophylaxis of central nervoussystem disorders such as states of anxiety, tension and depression,CNS-related sexual dysfunctions and sleep disturbances, and forcontrolling pathological disturbances of the intake of food, stimulantsand addictive substances.

Furthermore, the compounds according to the invention are also suitablefor regulating cerebral blood flow and are thus effective agents forcontrol of migraine. They are also suitable for prophylaxis and controlof sequelae of cerebral infarction (cerebral apoplexy) such as stroke,cerebral ischaemia and craniocerebral trauma. The compounds according tothe invention can likewise be employed for controlling states of painand tinnitus.

In addition, the compounds according to the invention haveantiinflammatory action and can therefore be used as antiinflammatoryagents for the treatment and/or prophylaxis of sepsis (SIRS), multipleorgan failure (MODS, MOF), inflammatory disorders of the kidney, chronicintestinal inflammations (IBD, Crohn's disease, UC), pancreatitis,peritonitis, rheumatoid disorders, inflammatory skin diseases andinflammatory eye diseases.

Furthermore, the compounds according to the invention can also be usedfor the treatment and/or prophylaxis of autoimmune diseases.

The compounds according to the invention are furthermore suitable forthe treatment and/or prophylaxis of fibrotic disorders of the internalorgans such as, for example, the lung, the heart, the kidney, the bonemarrow and in particular the liver, and also dermatological fibroses andfibrotic eye disorders. In the context of the present invention, theterm fibrotic disorders includes in particular the following terms:hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis,endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitialrenal fibrosis, fibrotic damage resulting from diabetes, bone marrowfibrosis and similar fibrotic disorders, scleroderma, morphea, keloids,hypertrophic scarring (also following surgical procedures), naevi,diabetic retinopathy, proliferative vitroretinopathy and disorders ofthe connective tissue (for example sarkoidosis).

The compounds according to the invention are furthermore suitable forcontrolling postoperative scarring, for example as a result of glaucomaoperations.

The compounds according to the invention can also be used cosmeticallyfor ageing and keratinized skin.

Moreover, the compounds according to the invention are suitable for thetreatment and/or prophylaxis of hepatitis, neoplasms, osteoporosis,glaucoma and gastroparesis.

The present invention further provides for the use of the compoundsaccording to the invention for the treatment and/or prophylaxis ofdisorders, in particular the disorders mentioned above.

The present invention further provides for the use of the compoundsaccording to the invention for the treatment and/or prophylaxis of heartfailure, angina pectoris, hypertension, pulmonary hypertension,ischaemias, vascular disorders, renal insufficiency, thromboembolicdisorders, fibrotic disorders and arteriosclerosis.

The present invention further provides the compounds according to theinvention for use in a method for the treatment and/or prophylaxis ofheart failure, angina pectoris, hypertension, pulmonary hypertension,ischaemias, vascular disorders, renal insufficiency, thromboembolicdisorders, fibrotic disorders and arteriosclerosis.

The present invention further provides for the use of the compoundsaccording to the invention for production of a medicament for thetreatment and/or prophylaxis of disorders, especially of theaforementioned disorders.

The present invention further provides for the use of the compoundsaccording to the invention for producing a medicament for the treatmentand/or prophylaxis of heart failure, angina pectoris, hypertension,pulmonary hypertension, ischaemias, vascular disorders, renalinsufficiency, thromboembolic disorders, fibrotic disorders andarteriosclerosis.

The present invention further provides a method for the treatment and/orprophylaxis of disorders, in particular the disorders mentioned above,using an effective amount of at least one of the compounds according tothe invention.

The present invention further provides a method for the treatment and/orprophylaxis of heart failure, angina pectoris, hypertension, pulmonaryhypertension, ischaemias, vascular disorders, renal insufficiency,thromboembolic disorders, fibrotic disorders and arteriosclerosis usingan effective amount of at least one of the compounds according to theinvention.

The compounds according to the invention can be employed alone or, ifrequired, in combination with other active compounds. The presentinvention further provides medicaments comprising at least one of thecompounds according to the invention and one or more further activecompounds, especially for the treatment and/or prophylaxis of theaforementioned disorders. Preferred examples of suitable activeingredient combinations include:

-   -   organic nitrates and NO donors, for example sodium        nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide        dinitrate, molsidomine or SIN-1, and inhaled NO;    -   compounds which inhibit the breakdown of cyclic guanosine        monophosphate (cGMP), for example inhibitors of        phosphodiesterases (PDE) 1, 2 and/or 5, in particular PDE 5        inhibitors such as sildenafil, vardenafil and tadalafil;    -   agents having antithrombotic activity, for example and with        preference from the group of platelet aggregation inhibitors, of        anticoagulants or of profibrinolytic substances;    -   active compounds lowering blood pressure, for example and        preferably from the group of calcium antagonists, angiotensin        AII antagonists, ACE inhibitors, endothelin antagonists, renin        inhibitors, alpha-receptor blockers, beta-receptor blockers,        mineralocorticoid receptor antagonists, and of diuretics; and/or    -   active compounds altering lipid metabolism, for example and with        preference from the group of thyroid receptor agonists,        cholesterol synthesis inhibitors such as, by way of example and        preferably, HMG-CoA reductase inhibitors or squalene synthesis        inhibitors, of ACAT inhibitors, CETP inhibitors, MTP inhibitors,        PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol        absorption inhibitors, lipase inhibitors, polymeric bile acid        adsorbents, bile acid reabsorption inhibitors and lipoprotein(a)        antagonists.

Agents having antithrombotic activity preferably mean compounds from thegroup of platelet aggregation inhibitors, of anticoagulants or ofprofibrinolytic substances.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a plateletaggregation inhibitor, by way of example and with preference aspirin,clopidogrel, ticlopidin or dipyridamole.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thrombin inhibitor,by way of example and with preference ximelagatran, dabigatran,melagatran, bivalirudin or clexane.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a GPIIb/IIIaantagonist such as, by way of example and with preference, tirofiban orabciximab.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a factor Xainhibitor, by way of example and with preference rivaroxaban (BAY59-7939), edoxaban (DU-176b), apixaban, otamixaban, fidexaban,razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982,EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 orSSR-128428.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with heparin or with a lowmolecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a vitamin Kantagonist, by way of example and with preference coumarin.

Hypotensive agents are preferably understood to mean compounds from thegroup of calcium antagonists, angiotensin AII antagonists, ACEinhibitors, endothelin antagonists, renin inhibitors, alpha-receptorblockers, beta-receptor blockers, mineralocorticoid receptorantagonists, and the diuretics.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a calcium antagonist,by way of example and with preference nifedipine, amlodipine, verapamilor diltiazem.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an alpha-1-receptorblocker, by way of example and with preference prazosin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a beta-receptorblocker, by way of example and with preference propranolol, atenolol,timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol,metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol,betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol,carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an angiotensin AIIantagonist, by way of example and with preference losartan, candesartan,valsartan, telmisartan or embusartan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACE inhibitor, byway of example and with preference enalapril, captopril, lisinopril,ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an endothelinantagonist, by way of example and with preference bosentan, darusentan,ambrisentan or sitaxsentan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a renin inhibitor, byway of example and with preference aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a mineralocorticoidreceptor antagonist, by way of example and with preferencespironolactone or eplerenone.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a loop diuretic suchas, for example, furosemide, torasemide, bumetanide and piretanide, withpotassium-sparing diuretics such as, for example, amiloride andtriamterene, with aldosterone antagonists such as, for example,spironolactone, potassium canrenoate and eplerenone and also thiazidediuretics such as, for example, hydrochlorothiazide, chlorthalidone,xipamide and indapamide.

Agents which modify lipid metabolism are preferably understood to meancompounds from the group of CETP inhibitors, thyroid receptor agonists,cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors orsqualene synthesis inhibitors, of ACAT inhibitors, MTP inhibitors,PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterolabsorption inhibitors, polymeric bile acid adsorbents, bile acidreabsorption inhibitors, lipase inhibitors and lipoprotein(a)antagonists.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a CETP inhibitor, byway of example and with preference dalcetrapib, BAY 60-5521, anacetrapiboder CETP vaccine (CETi-1).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thyroid receptoragonist, by way of example and with preference D-thyroxin,3,5,3′-triiodothyronin (T3), CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an HMG-CoA reductaseinhibitor from the class of statins, by way of example and withpreference lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin, rosuvastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a squalene synthesisinhibitor, by way of example and with preference BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACAT inhibitor, byway of example and with preference avasimibe, melinamide, pactimibe,eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an MTP inhibitor, byway of example and with preference implitapide, BMS-201038, R-103757 orITT-130.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-gamma agonist,by way of example and with preference pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-delta agonist,by way of example and with preference GW 501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a cholesterolabsorption inhibitor, by way of example and with preference ezetimibe,tiqueside or pamaqueside.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipase inhibitor, apreferred example being orlistat.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a polymeric bile acidadsorbent, by way of example and with preference cholestyramine,colestipol, colesolvam, CholestaGel or colestimide.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a bile acidreabsorption inhibitor, by way of example and with preferenceASBT(=IBAT) inhibitors, for example AZD-7806, S-8921, AK-105, BARI-1741,SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipoprotein(a)antagonist, by way of example and with preference gemcabene calcium(CI-1027) or nicotinic acid.

The present invention further provides medicaments which comprise atleast one compound according to the invention, typically together withone or more inert, non-toxic, pharmaceutically suitable auxiliaries, andfor the use thereof for the aforementioned purposes.

The compounds according to the invention can act systemically and/orlocally. For this purpose, they can be administered in a suitablemanner, for example by the oral, parenteral, pulmonal, nasal,sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivalor otic route, or as an implant or stent.

The compounds according to the invention can be administered inadministration forms suitable for these administration routes.

Administration forms which function according to the prior art, releasethe compounds according to the invention rapidly and/or in a modifiedmanner and contain the compounds according to the invention incrystalline and/or amorphized and/or dissolved form are suitable fororal administration, such as e.g. tablets (non-coated or coated tablets,for example with enteric coatings or coatings that dissolve in a delayedmanner or are insoluble and control the release of the compoundaccording to the invention), tablets or films/oblates,films/lyophilisates or capsules which disintegrate rapidly in the oralcavity (for example hard or soft gelatine capsules), sugar-coatedtablets, granules, pellets, powders, emulsions, suspensions, aerosols orsolutions.

Parenteral administration can bypass an absorption step (e.g.intravenously, intraarterially, intracardially, intraspinally orintralumbally) or include an absorption (e.g. intramuscularly,subcutaneously, intracutaneously, percutaneously or intraperitoneally).Suitable administration forms for parenteral administration includeinjection and infusion formulations in the form of solutions,suspensions, emulsions, lyophilisates or sterile powders.

For the other administration routes, suitable examples are inhalablemedicament forms (including powder inhalers, nebulizers), nasal drops,solutions or sprays, tablets, films/oblates or capsules for lingual,sublingual or buccal administration, suppositories, ear or eyepreparations, vaginal capsules, aqueous suspensions (lotions, shakingmixtures), lipophilic suspensions, ointments, creams, transdermaltherapeutic systems (e.g. patches), milk, pastes, foams, sprinklingpowders, implants or stents.

Preference is given to oral or parenteral administration, especiallyoral administration.

The compounds according to the invention can be converted to theadministration forms mentioned. This can be accomplished in a mannerknown per se by mixing with inert, non-toxic, pharmaceutically suitableauxiliaries. These auxiliaries include carriers (for examplemicrocrystalline cellulose, lactose, mannitol), solvents (e.g. liquidpolyethylene glycols), emulsifiers and dispersing or wetting agents (forexample sodium dodecylsulphate, polyoxysorbitan oleate), binders (forexample polyvinylpyrrolidone), synthetic and natural polymers (forexample albumin), stabilizers (e.g. antioxidants, for example ascorbicacid), dyes (e.g. inorganic pigments, for example iron oxides) andflavour and/or odour correctors.

In general, it has been found to be advantageous in the case ofparenteral administration to administer amounts of about 0.001 to 1mg/kg, preferably about 0.01 to 0.5 mg/kg, of body weight to achieveeffective results. In the case of oral administration, the dose is about0.001 to 2 mg/kg, preferably about 0.001 to 1 mg/kg, of body weight.

In spite of this, it may be necessary to deviate from the amountsspecified, specifically depending on body weight, administration route,individual behaviour towards the active ingredient, type of formulation,and time or interval of administration. For instance, less than theaforementioned minimum amount may be sufficient in some cases, while theupper limit mentioned has to be exceeded in other cases. In the case ofadministration of greater amounts, it may be advisable to divide theminto several individual doses over the day.

The working examples which follow illustrate the invention.

The percentages in the tests and examples which follow are, unlessindicated otherwise, percentages by weight; parts are parts by weight.Solvent ratios, dilution ratios and concentration figures forliquid/liquid solutions are each based on volume.

A. EXAMPLES Abbreviations and Acronyms

DCI direct chemical ionization (in MS)

DMF dimethylformamide

DMSO dimethyl sulphoxide

ESI electrospray ionization (in MS)

h hour(s)

HPLC high-pressure, high-performance liquid chromatography

LC/MS liquid chromatography-coupled mass spectrometry

min minute(s)

MS mass spectrometry

NMR nuclear magnetic resonance spectrometry

RT room temperature

R_(t) retention time (in HPLC)

t-Bu tert-butyl

TFA trifluoroacetic acid

THF tetrahydrofuran

v/v ratio by volume (of a solution)

HPLC and LC/MS Methods:

Method 1 (LC-MS):

Instrument: Waters ACQUITY SQD UPLC System; column: Waters Acquity UPLCHSS T3 1.8μ 50×1 mm; mobile phase A: 1 l of water+0.25 ml of 99%strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99%strength formic acid; gradient: 0.0 min 90% A→1.2 min 5% A→2.0 min 5% A;oven: 50° C.; flow rate: 0.40 ml/min; UV detection: 208-400 nm.

If, in the synthesis intermediates and working examples of the inventiondescribed below, a compound is given in the form of a salt of thecorresponding base or acid, the exact stoichiometric composition of sucha salt as obtained by the respective preparation and/or purificationprocess is generally not known. Unless specified in more detail,additions to names and structural formulae, such as “hydrochloride”,“trifluoroacetate”, “sodium salt” or “x HCl”, “x CF₃COOH”, “x Na⁺” arenot to be understood stoichiometrically in the case of such salts, buthave only descriptive character with regard to the salt-formingcomponents comprised therein.

This applies correspondingly if the synthesis intermediates and workingexamples or salts thereof were obtained by the preparation and/orpurification processes described in the form of solvates, for examplehydrates, whose stoichiometric composition (if of a defined type) is notknown.

Starting Materials and Intermediates:

Example 1A5-Fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridine-3-carboximidamideacetate

The preparation of the compound is described in WO2013/004785, example14A, pp. 69-70.

Example 2A Methyl 3,3-dicyano-2-(trifluoromethyl)acrylate

The synthesis of this compound is described in Journal of FluorineChemistry, 1991, vol. 51, #3 pp. 323-334.

Example 3A Methyl 2-(dicyanomethyl)-3,3,3-trifluoro-2-methylpropanoate

3.00 g (14.698 mmol) of Example 2A were dissolved in tetrahydrofuran (30ml) and the solution was cooled to 0° C. 7.35 ml (22.047 mmol) ofmethylmagnesium chloride (3M in THF) were then added dropwise such thatthe temperature did not exceed 5° C. After the addition had ended, themixture was stirred for another 10 min. 1N aqueous hydrochloric acid wasthen added to the reaction, and the mixture was subsequently extractedwith ethyl acetate. The phases were separated and the aqueous phase wasextracted two more times with ethyl acetate. The combined organic phaseswere washed with saturated aqueous sodium chloride solution, dried oversodium sulphate, filtered and concentrated. The crude product was thenchromatographed on silica gel (mobile phase: cyclohexane, thencyclohexane:ethyl acetate 9:1 (v:v)). Concentration gave 3.24 g (63% oftheory) of the title compound.

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=1.81 (s, 3H), 3.95 (s, 3H), 4.48 (s,1H).

Example 4A4-Amino-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

23.0 g (66.023 mmol) of Example 1A were initially charged intert-butanol (400 ml), and 13.43 g (119.683 mmol) of potassiumtert-butoxide were added. Subsequently, 21.079 g (95.746 mmol) ofExample 3A in tert-butanol (100 ml) were added and the mixture washeated at reflux overnight. After cooling, water was added and thereaction mixture was stirred at room temperature for 30 min. Theprecipitate formed was filtered off and washed with water and a littlediethyl ether. The solid was dried under high vacuum. This gave 16.1 gof the title compound (51% of theory).

LC-MS (Method 1): R_(t)=0.95 min; MS (ESIpos): m/z=477 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.72 (s, 3H), 5.96 (s, 2H), 7.10 (brs, 2H), 7.42-7.48 (m, 1H), 7.75-7.80 (m, 1H), 8.27 (d, 1H), 8.68 (dd,1H), 8.86 (dd, 1H), 11.60 (br s, 1H).

Example 5A2-{5-Fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-4-iodo-5-methyl-5-(trifluoromethyl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

798 μl (5.930 mmol) of isopentyl nitrite and 286 μl (3.558 mmol) ofdiiodomethane were added to 565 mg (1.186 mmol) of Example 4A in dioxane(15 ml), and the mixture was heated at 85° C. for 4 h. After cooling,the mixture was concentrated under reduced pressure, the residue wastaken up in dichloromethane, kieselguhr was added and the mixture wasthen concentrated under reduced pressure. The crude compound adsorbed onkieselguhr was then chromatographed on silica gel (mobile phase:cyclohexane:ethyl acetate gradient). Concentration gave 297 mg (42% oftheory) of the title compound.

LC-MS (Method 1): R_(t)=1.19 min; MS (ESIpos): m/z=588 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.81 (s, 3H), 6.04 (s, 2H), 7.43-7.47(m, 1H), 7.77-7.82 (m, 1H), 8.26 (d, 1H), 8.47 (dd, 1H), 8.76 (dd, 1H),12.41 (br s, 1H).

WORKING EXAMPLES Example 12-{5-Fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

In a microwavable reaction vessel, 293 mg (0.462 mmol, purity about 92%)of Example 5A were dissolved in 1-methyl-2-pyrrolidone (4.5 ml), and 126μl (1.409 mmol) of 3,3,3-trifluoropropyl-1-amine were added. The vesselwas then sealed with a septum and heated at 150° C. in the microwave for3 h. After cooling, the reaction mixture was purified by preparativeHPLC (acetonitrile:water (+0.05% formic acid) gradient). This gave 168mg of the title compound (62% of theory, purity 97%).

LC-MS (Method 1): R_(t)=1.15 min; MS (EIpos): m/z=573 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.73 (s, 3H), 2.64-2.71 (m, 2H),3.79-3.93 (m, 2H), 5.99 (s, 2H), 6.91 (t, 1H), 7.42-7.46 (m, 1H), 7.78(t, 1H), 8.28 (d, 1H), 8.46 (dd, 1H), 8.71 (s br, 1H), 11.71 (br s, 1H).

Separation into Enantiomers:

301 mg of racemate (combined amount Example 1 from 2 different batches)were separated into the enantiomers by preparative HPLC (mobile phase:(isohexane/ethanol 30/70 (v/v), flow rate 15 ml/min, temperature 40° C.,wavelength: 220 nm) on a chiral phase (Daicel Chiralpak AZ-H, 5 μM,250×20 mm).

Example 1-1 Enantiomer 1(5S)-2-{5-Fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

Yield: 138 mg

R_(t)=4.056 min; ee>99% [analytical HPLC, mobile phase:isohexane/ethanol 30/70 (v/v), flow rate 1 ml/min, temperature 40° C.,wavelength: 220 nm, on a chiral phase (Daicel Chiralpak AZ-H, 5 μM250×4.6 mm)].

Single crystal X-ray structural analysis confirmed the S configurationof this enantiomer.

Example 1-2 Enantiomer 2(5R)-2-{5-Fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

Yield: 145 mg

R_(t)=5.576 min; ee>99% [analytical HPLC, mobile phase:isohexane/ethanol 30/70 (v/v), flow rate 1 ml/min, temperature 40° C.,wavelength: 220 nm, on a chiral phase (Daicel Chiralpak AZ-H, 5 μM250×4.6 mm)].

B. ASSESSMENT OF PHARMACOLOGICAL EFFICACY

Hereinbelow, the following abbreviations are used:

BSA bovine serum albumin

EDTA ethylenediaminetetraacetic acid

μCi microcurie

Tris tris(hydroxymethyl)aminomethane

The pharmacological effect of the compounds according to the inventioncan be shown in the following assays:

B-1. Vasorelaxant Effect In Vitro

Rabbits are stunned by a blow to the neck and exsanguinated. The aortais removed, freed from adhering tissue and divided into rings of a widthof 1.5 mm. The rings are placed individually under an initial tension in5 ml organ baths with Krebs-Henseleit solution which is at 37° C., isgassed with carbogen and has the following composition (in each casemM): sodium chloride: 119; potassium chloride: 4.8; calcium chloridedihydrate: 1; magnesium sulphate heptahydrate: 1.4; potassiumdihydrogenphosphate: 1.2; sodium bicarbonate: 25; glucose: 10. Thecontractile force is determined with Statham UC2 cells, amplified anddigitalized using A/D transducers (DAS-1802 HC, Keithley InstrumentsMunich), and recorded in parallel on linear recorders. To produce acontraction, phenylephrine is added to the bath cumulatively inincreasing concentration. After several control cycles, the substance tobe investigated is added in each further run in increasing dosage ineach case, and the height of the contraction achieved is compared withthe height of the contraction reached in the last preceding run. This isused to calculate the concentration needed to reduce the magnitude ofthe control value by 50% (IC₅₀ value). The standard administrationvolume is 5 μl; the DMSO content in the bath solution corresponds to0.1%.

Representative IC₅₀ values for the compounds according to the inventionare shown in the table below (Table 1):

TABLE 1 Example No. IC₅₀ [nM] 1-1 265 1-2 237B-2. Effect on a Recombinant Guanylate Cyclase Reporter Cell Line

The cellular activity of the compounds according to the invention isdetermined using a recombinant guanylate cyclase reporter cell line, asdescribed in F. Wunder et al., Anal. Biochem. 339, 104-112 (2005).

Representative values (MEC=minimum effective concentration) for thecompounds according to the invention are shown in the table below (Table2):

TABLE 2 MEC Example [μM] 1-1 0.1 1-2 1.0B-3. Radiotelemetric Measurement of Blood Pressure on ConsciousSpontaneously Hypertensive Rats

A commercially available telemetry system from DATA SCIENCESINTERNATIONAL DSI, USA, is employed for the blood pressure measurementon conscious rats described below.

The system consists of 3 main components:

-   -   implantable transmitters (Physiotel® telemetry transmitter)    -   receivers (Physiotel® receiver) which are linked via a        multiplexer (DSI Data Exchange Matrix) to a    -   data acquisition computer.

The telemetry system makes it possible to continuously record bloodpressure, heart rate and body motion of conscious animals in their usualhabitat.

Animal Material

The investigations are carried out on adult female spontaneouslyhypertensive rats (SHR Okamoto) with a body weight of >200 g. SHR/NCrlfrom the Okamoto Kyoto School of Medicine, 1963 were a cross of maleWistar Kyoto rats with highly elevated blood pressure and female ratshaving a slightly elevated blood pressure and at F13 handed over to theU.S. National Institutes of Health.

After transmitter implantation, the experimental animals are housedsingly in type 3 Makrolon cages. They have free access to standard feedand water.

The day/night rhythm in the experimental laboratory is changed by theroom lighting at 6.00 am and at 7.00 pm.

Transmitter Implantation

The telemetry transmitters TA11 PA-C40 used are surgically implantedunder aseptic conditions in the experimental animals at least 14 daysbefore the first experimental use. The animals instrumented in this waycan be employed repeatedly after the wound has healed and the implanthas settled.

Anaesthesia is initiated with O₂+N₂O gas 30:50 with 5% isoflurane in aflow vessel.

Following initiation of anaesthesia, the anaesthesia mask is attached tothe animal, which is on a warming plate, and 1.8% of isoflurane areadministered for anaesthesiais maintenance. The animals are shaved anddisinfected over a large area of their abdomen. After the abdominalcavity has been opened along the linea alba, the liquid-filled measuringcatheter of the system is inserted into the descending aorta in thecranial direction above the bifurcation and fixed with tissue glue(VetBonD™, 3M). The transmitter housing is fixed intraperitoneally tothe abdominal wall muscle, and layered closure of the wound isperformed.

Post-operatively, an antibiotic (Oxytetracyclin® 10%, 60 mg/kg s.c.,0.06 ml/100 g body weight, Beta-Pharma GmbH & Co, Germany) for infectionprophylaxis and an analgesic (Rimadyl®, 4 mg/kg s.c., Pfizer, Germany)are administered.

Substances and Solutions

Unless indicated otherwise, the substances to be investigated areadministered orally by gavage in each case to a group of animals (n=6).The test substances are dissolved in suitable solvent mixtures, orsuspended in 0.5% strength Tylose, appropriate for an administrationvolume of 2 ml/kg of body weight.

A solvent-treated group of animals is employed as control.

Test Procedure

The telemetry measuring unit present is configured for 24 animals. Eachexperiment is recorded under an experiment number (Vyear month day).

Each of the instrumented rats living in the system is assigned aseparate receiving antenna (1010 Receiver, DSI).

The implanted transmitters can be activated externally by means of anincorporated magnetic switch and are switched to transmission in therun-up to the experiment. The signals emitted can be detected online bya data acquisition system (Dataquest™ A.R.T. for WINDOWS, DSI) andprocessed accordingly. The data are stored in each case in a filecreated for this purpose and bearing the experiment number.

In the standard procedure, the following are measured for 10-secondperiods in each case:

-   -   systolic blood pressure (SBP)    -   diastolic blood pressure (DBP)    -   mean arterial pressure (MAP)    -   heart rate (HR)    -   activity (ACT).

The acquisition of measurements is repeated under computer control at5-minute intervals. The source data obtained as absolute value arecorrected in the diagram with the currently measured barometric pressure(Ambient Pressure Reference Monitor; APR-1) and stored as individualdata. Further technical details are given in the extensive documentationfrom the manufacturing company (DSI).

Unless indicated otherwise, the test substances are administered at 9.00am on the day of the experiment. Following the administration, theparameters described above are measured over 24 hours.

Evaluation

After the end of the experiment, the acquired individual data are sortedusing the analysis software (DATAQUEST™ A.R.T.™ ANALYSIS). The blankvalue is assumed to be the time 2 hours before administration, and sothe selected data set encompasses the period from 7.00 am on the day ofthe experiment to 9.00 am the following day.

The data are smoothed over a presettable time by determination of theaverage (30-minute average) and transferred as a text file to a storagemedium. The measured values presorted and compressed in this way aretransferred into Excel templates and tabulated. For each day of theexperiment, the data obtained are stored in a dedicated file bearing thenumber of the experiment. Results and test protocols are filed sorted bynumbers.

Representative values for the compounds according to the invention areshown in the table below (Table 3):

TABLE 3 Example 1-1 Dosage: 0.3 mg/kg Dosage: Vehicle p.o. 0.03 mg/kg 2ml/kg mean mg/kg hours after mean blood blood mean blood substancepressure pressure pressure administration (mmHg) (mmHg) (mmHg) 0 143.6138.7 148.8 1 142.0 116.3 133.5 2 138.5 106.8 127.3 3 141.2 107.2 128.84 141.5 105.5 132.3 5 138.7 106.2 126.0 6 136.7 106.8 124.5 7 147.8101.7 138.8 8 154.7 111.3 143.8 9 143.3 109.0 136.5 10 150.8 113.3 143.811 149.2 114.8 141.7 12 150.7 112.0 141.7 13 151.7 117.2 150.5 14 148.8115.7 150.8 15 155.3 117.8 153.8 16 150.3 111.5 145.7 17 155.5 121.7155.3 18 156.7 132.3 151.2 19 160.2 117.0 146.3 20 144.5 110.7 140.2 21151.5 124.0 142.2 22 145.5 125.5 142.8 23 165.0 139.0 143.0 24 171.5150.5 143.2

REFERENCES

-   Klaus Witte, Kai Hu, Johanna Swiatek, Claudia Müssig, Georg Ertl and    Björn Lemmer: Experimental heart failure in rats: effects on    cardiovascular circadian rhythms and on myocardial β-adrenergic    signaling. Cardiovasc Res 47 (2): 203-405, 2000; Kozo Okamoto:    Spontaneous hypertension in rats. Int Rev Exp Pathol 7: 227-270,    1969; Maarten van den Buuse: Circadian Rhythms of Blood Pressure,    Heart Rate, and Locomotor Activity in Spontaneously Hypertensive    Rats as Measured With Radio-Telemetry. Physiology & Behavior 55(4):    783-787, 1994    B-4. Determination of Pharmacokinetic Parameters Following    Intravenous and Oral Administration

The pharmacokinetic parameters of the compounds of the formula (I)according to the invention are determined in male CD-1 mice, male Wistarrats and female beagles. Intravenous administration in the case of miceand rats is effected by means of a species-specific plasma/DMSOformulation, and in the case of dogs by means of a water/PEG400/ethanolformulation. In all species, oral administration of the dissolvedsubstance is performed via gavage, based on a water/PEG400/ethanolformulation. The removal of blood from rats is simplified by inserting asilicone catheter into the right Vena jugularis externa prior tosubstance administration. The operation is effected at least one dayprior to the experiment with isofluran anaesthesia and administration ofan analgesic (atropine/rimadyl (3/1) 0.1 ml s.c.). The blood is taken(generally more than 10 time points) within a time window includingterminal time points of at least 24 to a maximum of 72 hours aftersubstance administration. The blood is removed into heparinized tubes.The blood plasma is then obtained by centrifugation; if required, it canbe stored at −20° C. until further processing.

An internal standard (which may also be a chemically unrelatedsubstance) is added to the samples of the compounds of the formula (I)according to the invention, calibration samples and qualifiers, and thisis followed by protein precipitation using excess acetonitrile. Additionof a buffer solution matched to the LC conditions, and subsequentvortexing, is followed by centrifugation at 1000 g. The supernatant isanalysed by means of LC-MS/MS using C18 reversed-phase columns andvariable mobile phase mixtures. The substances are quantified via thepeak heights or areas from extracted ion chromatograms of specificselected ion monitoring experiments.

The plasma concentration/time plots determined are used to calculate thepharmacokinetic parameters such as AUC (area under the curve), C_(max),t_(1/2) (terminal half life), F (bioavailability), MRT (mean residencetime) and CL (clearance), using a validated pharmacokinetic calculationprogramme.

Since the substance quantification is performed in plasma, it isnecessary to determine the blood/plasma distribution of the substance inorder to be able to adjust the pharmacokinetic parameterscorrespondingly. For this purpose, a defined amount of substance isincubated in heparinized whole blood of the species in question in arocking roller mixer for 20 min. After centrifugation at 1000 g, theplasma concentration is measured (by means of LC-MS/MS; see above) anddetermined by calculating the ratio of the C_(blood)/C_(plasma) value.

Table 4 shows data of representative compounds of the present inventionfollowing intravenous administration of 0.3 mg/kg and oraladministration of 1 mg/kg in rats:

TABLE 4 Example 1-1 AUC_(norm) [kg · h/l] 1.77 CL_(blood) [l/h/kg] 0.70MRT [h] 6.6 t_(1/2) [h] 5.9 F [%] 98.8B-5. Metabolic Study

To determine the metabolic profile of the compounds according to theinvention, they are incubated with recombinant human cytochrome P450(CYP) enzymes, liver microsomes or primary fresh hepatocytes fromvarious animal species (e.g. rats, dogs), and also of human origin, inorder to obtain and to compare information about a very substantiallycomplete hepatic phase I and phase II metabolism, and about the enzymesinvolved in the metabolism.

The compounds according to the invention were incubated with aconcentration of about 0.1-10 μM. To this end, stock solutions of thecompounds according to the invention having a concentration of 0.01-1 mMin acetonitrile were prepared, and then pipetted with 1:100 dilutioninto the incubation mixture. Liver microsomes and recombinant enzymeswere incubated at 37° C. in 50 mM potassium phosphate buffer pH 7.4 withand without NADPH-generating system consisting of 1 mM NADP⁺, 10 mMglucose-6-phosphate and 1 unit glucose-6-phosphate dehydrogenase.Primary hepatocytes were incubated in suspension in Williams E medium,likewise at 37° C. After an incubation time of 0-4 h, the incubationmixtures were quenched with acetonitrile (final concentration about 30%)and the protein was centrifuged off at about 15 000×g. The samples thusstopped were either analysed directly or stored at −20° C. untilanalysis.

The analysis is effected by means of high-performance liquidchromatography with ultraviolet and mass spectrometry detection(HPLC-UV-MS/MS). To this end, the supernatants of the incubation samplesare chromatographed with suitable C18 reversed-phase columns andvariable mobile phase mixtures of acetonitrile and 10 mM aqueousammonium formate solution or 0.05% formic acid. The UV chromatograms inconjunction with mass spectrometry data serve for identification,structural elucidation and quantitative estimation of the metabolites,and for quantitative metabolic assessment of the compound according tothe invention in the incubation mixtures.

B-6. Inhibition of Bovine Phosphodiesterase 6 (PDE 6)

PDE 6 is purified from external photoreceptor segments of bovine retina(ROS), activated by mild trypsination and purified further by ionexchange chromatography using a Mono Q column. Fractions having PDE 6activity are combined (PDE 6 preparation) and stored at −80° (I. Saenzde Tejada et al., International Journal of Impotence Research 2001, 13,282-290). The in vitro effect of test substances on bovine PDE 6 isdetermined using the commercially available 3H-cGMP ScintillationProximity Assay (SPA) from Perkin Elmer. The reaction (20 mM, 37° C.)comprises serial dilution series of the test substances in DMSO and PDE6 preparation (typical dilution 1:100,000), [8⁻³H]guanosine 3′,5′-cyclicphosphate (0.25 μCi/mL; Perkin Elmer) and unlabelled cGMP (10 μM) inassay buffer (50 mM Tris/HCl pH 7.5; 140 mM NaCl; 8.3 mM MgCl₂; 1.7 mMEDTA; 0.02% BSA). IC₅₀ values are determined by plotting the substanceconcentration against the percent PDE 6 inhibition determined (Wunder etal. Molecular Pharmacology 2005, 68, 1775-1781).

Representative IC₅₀ values for the compounds according to the inventionare shown in the table below (Table 5):

TABLE 5 Example No. IC₅₀ [nM] 1-1 220 1-2 1400B-7. Determination of Organ-Protective Effects in a Long-Term Experimenton Rats

The organ-protective effects of the sGC stimulators were shown in atherapeutically relevant “low nitric oxide (NO)/high renin” hypertensionmodel in rats. The study was conducted following a recently publishedarticle (Sharkovska Y, Kalk P, Lawrenz B, Godes M, Hoffmann L S,Wellkisch K, Geschka S, Relle K, Hocher B, Stasch J P. NO-independentstimulation of soluble guanylate cyclase reduces target organ damage inlow- and high-renin models of hypertension. J. Hypertension. 2010; 28:1666-1675). This involved treating renin-transgenic rats (TGR(mRen2)27)to which the NO synthase inhibitor L-NAME had been administered viadrinking water simultaneously with an sGC stimulator or vehicle overseveral weeks. Haemodynamic and renal parameters were determined duringthe treatment period. At the end of the long-term study, organprotection (kidney, lung, heart, aorta) was shown by histopathologicalstudies, biomarkers, expression analyses and cardiovascular plasmaparameters.

C. WORKING EXAMPLES OF PHARMACEUTICAL COMPOSITIONS

The compounds according to the invention can be converted topharmaceutical formulations as follows:

Tablet:

Composition:

100 mg of the compound according to the invention, 50 mg of lactose(monohydrate), 50 mg of corn starch (native), 10 mg ofpolyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg ofmagnesium stearate.

Tablet weight 212 mg, diameter 8 mm, radius of curvature 12 mm.

Production:

The mixture of compound according to the invention, lactose and starchis granulated with a 5% solution (w/w) of the PVP in water. The granulesare dried and mixed with the magnesium stearate for 5 minutes. Thismixture is pressed with a conventional tableting press (for tabletdimensions see above). The guide value used for the pressing is apressing force of 15 kN.

Suspension which can be Administered Orally:

Composition:

1000 mg of the compound according to the invention, 1000 mg of ethanol(96%), 400 mg of Rhodigel® (xanthan gum from FMC, Pa., USA) and 99 g ofwater.

A single dose of 100 mg of the compound according to the inventioncorresponds to 10 ml of oral suspension.

Production:

The Rhodigel is suspended in ethanol and the compound according to theinvention is added to the suspension. The water is added while stirring.The mixture is stirred for about 6 h until swelling of the Rhodigel iscomplete.

Solution for Oral Administration:

Composition:

500 mg of the compound according to the invention, 2.5 g of polysorbateand 97 g of polyethylene glycol 400. A single dose of 100 mg of thecompound according to the invention corresponds to 20 g of oralsolution.

Production:

The compound according to the invention is suspended in the mixture ofpolyethylene glycol and polysorbate while stirring. The stirringoperation is continued until dissolution of the compound according tothe invention is complete.

i.v. Solution:

The compound according to the invention is dissolved in a concentrationbelow the saturation solubility in a physiologically acceptable solvent(e.g. isotonic saline, glucose solution 5% and/or PEG 400 solution 30%).The solution is subjected to sterile filtration and dispensed intosterile and pyrogen-free injection vessels.

The invention claimed is:
 1. A compound having the systematic name2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-oneand the structural formula (I)

or a salt thereof.
 2. An enantiomer of the compound of claim 1 havingthe systematic name(5R)-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-oneand the structural formula (I-A)

or salt thereof.
 3. An enantiomer of the compound of claim 1, having thesystematic name(5S)-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-oneand the structural formula (I-B)

or a salt thereof.
 4. A pharmaceutical composition comprising a compoundof claim 1 and an inert, non-toxic, pharmaceutically suitable auxiliary.5. A pharmaceutical composition comprising a compound of claim 2 and aninert, non-toxic, pharmaceutically suitable auxiliary.
 6. Apharmaceutical composition comprising a compound of claim 3 and aninert, non-toxic, pharmaceutically suitable auxiliary.
 7. Thepharmaceutical composition of claim 4, further comprising an activecompound selected from the group consisting of an organic nitrate, an NOdonor, a cGMP-PDE inhibitor, an agent having antithrombotic activity, anagent lowering blood pressure, and an agent altering lipid metabolism.8. The pharmaceutical composition of claim 5, further comprising anactive compound selected from the group consisting of an organicnitrate, an NO donor, a cGMP-PDE inhibitor, an agent havingantithrombotic activity, an agent lowering blood pressure, and an agentaltering lipid metabolism.
 9. The pharmaceutical composition of claim 6,further comprising an active compound selected from the group consistingof an organic nitrate, an NO donor, a cGMP-PDE inhibitor, an agenthaving antithrombotic activity, an agent lowering blood pressure, and anagent altering lipid metabolism.
 10. A process for preparing a compoundof claim 1, comprising converting a compound of the formula (II)

in an inert solvent using isopentyl nitrite and a halogen equivalentinto a compound of the formula (III)

reacting the compound of formula (III) in an inert solvent, optionallyin the presence of a suitable base, with a compound of the formula (IV)

to give a compound of the formula (I)

and optionally converting the compound of the formula (I) with a (i)solvent and/or (ii) acid or base into solvate, salt and/or solvate of asalt thereof.
 11. The process of claim 10, further comprising separatingthe compound of formula (I) into enantiomers thereof.
 12. A method forthe treatment of heart failure, angina pectoris, hypertension, pulmonaryhypertension, ischaemias, vascular disorders, renal insufficiency,thromboembolic disorders, fibrotic disorders and arteriosclerosiscomprising administering to a human or animal in need thereof aneffective amount of at least one compound of claim
 1. 13. A method forthe treatment of heart failure, angina pectoris, hypertension, pulmonaryhypertension, ischaemias, vascular disorders, renal insufficiency,thromboembolic disorders, fibrotic disorders and arteriosclerosiscomprising administering to a human or animal in need thereof aneffective amount of at least one compound of claim
 2. 14. A method forthe treatment of heart failure, angina pectoris, hypertension, pulmonaryhypertension, ischaemias, vascular disorders, renal insufficiency,thromboembolic disorders, fibrotic disorders and arteriosclerosiscomprising administering to a human or animal in need thereof aneffective amount of at least one compound of claim
 3. 15. A method forthe treatment of heart failure, angina pectoris, hypertension, pulmonaryhypertension, ischaemias, vascular disorders, renal insufficiency,thromboembolic disorders, fibrotic disorders and arteriosclerosiscomprising administering to a human or animal in need thereof aneffective amount of the pharmaceutical composition of claim
 4. 16. Amethod for the treatment of heart failure, angina pectoris,hypertension, pulmonary hypertension, ischaemias, vascular disorders,renal insufficiency, thromboembolic disorders, fibrotic disorders andarteriosclerosis comprising administering to a human or animal in needthereof an effective amount of the pharmaceutical composition of claim5.
 17. A method for the treatment of heart failure, angina pectoris,hypertension, pulmonary hypertension, ischaemias, vascular disorders,renal insufficiency, thromboembolic disorders, fibrotic disorders andarteriosclerosis comprising administering to a human or animal in needthereof an effective amount of the pharmaceutical composition of claim6.